Our Section has developed protocols for the treatment and study of thoracic malignancies including mesothelioma, metastatic disease to the lungs, and esophageal cancer. After performing a Phase I trial of phototherapy for pleural disease (Ann Surg Oncol 1994; 1:28-37) and a Phase II trial of immunochemotherapy (cisplatin, interferon, and tamoxifen: CIT) for malignant pleural mesothelioma(MPM) (Ann Surg Oncol 1995;2:214-220), a Phase III trial has been ongoing which compares maximal debulking surgery, intraoperative photodynamic therapy, and postoperative CIT to maximal debulking surgery and postoperative CIT. This program has accumulated 46 patients with MPM since July 1993, with a projected total accrual of 48 patients per arm. At this time there are no significant differences in survival or time to recurrence between the two groups. We have also performed a Phase I trial investigating the use of radiation therapy and concurrent paclitaxel in 18 other patients, seventeen of which had MPM. This study demonstrated the feasibility of paclitaxel delivered as a 120 hour continuous infusion at 105 mg/m2 with concurrent radiotherapy. Benchwork investigations resulting from the clinical trials in mesothelioma have included the development of 20 new cell lines, which are being evaluated for growth factor mechanisms including the insulin growth factors, and the presence of CD44, the hyaluronic acid binding receptor. We are also expanding our investigations into the relationship of DNA viruses such as SV40 and MPM carcinogenesis, after our original description that 60% of our human MPM specimens had DNA for T-antigen. These investigations include analysis of sera for antibodies to T-antigen, PCR amplification of the carboxyl terminal end of T-antigen DNA from human MPM, and T-antigen-p53 relationships. In animal models of mesothelioma, our laboratory has reported on the efficacy of thymidine kinase gene therapy using retroviral vectors, and this is continuing using an adenoviral RSV-TK construct. Delayed tumor development by targeting the IGF-l receptor with antisense technology has also been described. For 18 patients with pulmonary metastases, a Phase I trial of isolated lung perfusion with human recombinant tumor necrosis factor has demonstrated the feasibility and safety of this method of cytokine delivery for doses up to 9 mg. A neoadjuvant trial of interferon, cisplatinum, 5-FU, and leucovorin is also ongoing in which labelling index of esophageal cancer, utility of endoesophageal ultrasound, and response rates are being studied.